Association of ORMDL3 with rhinovirus-induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes

AbstractType I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.

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An essential dimer-forming subregion of the endoplasmic reticulum stress sensor Ire1

Biochemical Journal ◽

10.1042/bj20050640 ◽

2005 ◽

Vol 391 (1) ◽

pp. 135-142 ◽

Cited By ~ 27

Author(s):

Daisuke Oikawa ◽

Yukio Kimata ◽

Masato Takeuchi ◽

Kenji Kohno

Keyword(s):

Endoplasmic Reticulum ◽

Recombinant Protein ◽

Endoplasmic Reticulum Stress ◽

Transmembrane Protein ◽

Type I ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Recombinant Fragments ◽

Made In

The luminal domain of the type I transmembrane protein Ire1 senses endoplasmic reticulum stress by an undefined mechanism to up-regulate the signalling pathway for the unfolded protein response. Previously, we proposed that the luminal domain of yeast Ire1 is divided into five subregions, termed subregions I–V sequentially from the N-terminus. Ire1 lost activity when internal deletions of subregion II or IV were made. In the present paper, we show that partial proteolysis of a recombinant protein consisting of the Ire1 luminal domain suggests that subregions II–IV are tightly folded. We also show that a recombinant protein of subregions II–IV formed homodimers, and that this homodimer formation was impaired by an internal deletion of subregion IV. Furthermore, recombinant fragments of subregion IV exhibited a self-binding ability. Therefore, although its sequence is little conserved evolutionarily, subregion IV plays an essential role to promote Ire1 dimer formation.

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435 Autocrine IFN-k maintains baseline type I interferon responses in keratinocytes in a Tyk2 dependent manner

Journal of Investigative Dermatology ◽

10.1016/j.jid.2016.06.455 ◽

2016 ◽

Vol 136 (9) ◽

pp. S234

Author(s):

M. Sarkar ◽

L.C. Tsoi ◽

X. Xing ◽

L. Yun ◽

P. Harms ◽

...

Keyword(s):

Type I Interferon ◽

Type I ◽

Dependent Manner ◽

Interferon Responses

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Type I interferon responses to ischemic injury begin in the bone marrow of mice and humans and depend on Tet2, Nrf2, and Irf3

10.1101/765404 ◽

2019 ◽

Cited By ~ 1

Author(s):

David M. Calcagno ◽

Richard P. Ng ◽

Avinash Toomu ◽

Claire Zhang ◽

Kenneth Huang ◽

...

Keyword(s):

Bone Marrow ◽

Type I Interferon ◽

Tissue Injury ◽

Type I ◽

Blood Neutrophils ◽

Clinical Biomarker ◽

Acute Mi ◽

Molecular Patterns ◽

Interferon Responses ◽

Myeloid Progenitors

AbstractSterile tissue injury locally activates innate immune responses via interactions with damage associated molecular patterns (DAMPs). Here, by analyzing ∼120K single cell transcriptomes after myocardial infarction (MI) in mice and humans, we show neutrophil and monocyte subsets induce type I interferon (IFN) stimulated genes (ISGs) in myeloid progenitors of the bone marrow, far from the site of injury. In patients with acute MI, peripheral blood neutrophils and monocytes express ISGs at levels far beyond healthy individuals and comparable to patients with lupus. In the bone marrow of Tet2-/- mice, ISGs are spontaneously induced in myeloid progenitors and their progeny. In the heart, IFN responses are negatively regulated by Ccr2- resident macrophages in a Nrf2-dependent fashion. Our results show post-MI IFN signaling begins in the bone marrow, implicate multiple transcription factors in its regulation (Tet2, Irf3, Nrf2), and provide a clinical biomarker (ISG score) for studying post-MI IFN signaling in patients.

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